“Our study demonstrates the high sensitivity of [gallium Ga-68 dotatate] in the localization of [ectopic Cushing’s syndrome], for both occult primary tumors and metastatic lesions,” the researchers wrote. “Importantly, the use of [gallium Ga-68 dotatate] impacted clinical management in 64% of patients with [ectopic Cushing’s syndrome] overall.” The researche […]

The 11th annual Pituitary Day will take place on October 19, 2019 Patients living with pituitary disorders can hear lectures from our pituitary specialists, see movies of pituitary surgeries and hear from other patients about their experience living with pituitary disease and undergoing surgery.

Cynthia is from Ruckersville, VA. She is testing for Cushing's due to many symptoms. tested for CD because after exhaustive research on AVN (Avascular Necrosis) related to other diseases. I have four known areas of AVN & after seeing the symptoms of CD, I realized may have this. I also have numerous other diseases Lupus, Sojgrens, Hypothyroid, High […]

Today is the Thirteenth Anniversary of my kidney cancer surgery. These thirteen years have been bonus years for me. For my cancer stage, the 5-year survival rate was 81% and I’ve made it more than twice that long – so far.

Kathy was diagnosed with a pituitary tumor in 1991. At the time the only symptom she was aware of was a severe headache. She had a transsphenoidal resection followed by radiation therapy for 23 days. They said they could not remove all of the tumor.

Sadly, we lost another Cushing’s patient on Friday, May 9, 2014. Melinda was a member of the Cushing’s Help message boards since Jun 24, 2007. She was only 25 and left behind a young son and many loving family members.

He died of a presumed heart attack. September 19, 2015 he said "'I was diagnosed hypertensive way back when I was 20. The condition remained for years, and became more acute with my cushings pit tumor. I still have high blood pressure, partially teated with three meds. I'll have to consult my doc and see if this may also be an issue."

'My name is Caroline and I dont post often but have met a few of you guys and read the board regularly, it has definitely been a godsend to cushies everywhere. The reason I am writing tonight is I have just received devastating information about a dear friend of mine, and a woman some of you may have met during testing. Her name is Kathryn Miller and sh […]

Pituitary tumors, like those that cause Cushing’s disease, have significant effects on a patient’s physical, mental, and social health, all of which influence their work status and health-related quality of life. However, the effects of the disease on work status is relatively under-investigated, investigators report.

Here, researchers evaluated the work disability among patients who were treated for pituitary tumors in an attempt to understand the impact of disease diagnosis and treatment on their social participation and ability to maintain a paying job.

In their study, researchers examined 241 patients (61% women) with a median age of 53 years. The majority (27%) had non-functioning pituitary tumors, which do not produce excess hormones, but patients with acromegaly, Cushing’s disease, prolactinomas, and Rathke’s cleft cyst also were included.

Participants were asked to complete questionnaires to evaluate their health-related quality of life and disease-specific impact on their work capabilities. Each participant completed a set of five questionnaires.

Participants also reported their hormonal status and demographic data, including gender, age, education, and marital status. Specific information, such as disease diagnosis, treatment, and tumor type was obtained from their medical records.

SF-HLQ was used to obtain information on the participants’ employment and their work attendance. Employment was either paid or unpaid. (Participation in household chores was considered not having a paid job.)

WRFQ is a 27-question survey that determines work disability regarding being able to meet the productivity, physical, emotional, social, and flexible demands. A higher score indicates low self-perceived work disability.

Overall, 28% of patients did not have a paid job, but the rates increased to 47% among those with Cushing’s disease. Low education, hormonal deficits, and being single were identified as the most common determinants of not having a paid job among this population.

Further analysis revealed that more patients with Cushing’s disease and acromegaly had undergone radiotherapy. They also had more hormonal deficits than others with different tumor types.

Overall, patients with a paid job reported working a median of 36 hours in one week and 41% of those patients missed work an average of 27 days during the previous year. Health-related problems during work also were reported by 39% with a paid job.

Finally, health-related quality of life was determined using two questionnaires: SF-36 and EQ-5D. The physical, mental, and emotional well being was measured with SF-36, while ED-5D measured the health outcome based on the impact of pain, mobility, self-care, usual activities, discomfort, and anxiety or depression. In both SF-36 and EQ-5D, a higher score indicates a better health status.

Statistical analysis revealed that the quality of life was significantly higher in patients with a job. Overall, patients with a paid job reported better health status and higher quality of life than those without a paid job.

Although 40% of the patients reported being bothered by health-related problems in the past year, only 12% sought the help of an occupational physician, the researchers reported.

“Work disability among patients with a pituitary tumor is substantial,” investigators said.

“The determinants and difficulties at work found in this study could potentially be used for further research, and we advise healthcare professionals to take these results into consideration in the clinical guidance of patients,” they concluded.

Functional remission did not occur in most patients with Cushing syndrome who were considered to be in biochemical and clinical remission, according to a study published in Endocrine. This was evidenced by their quality of life, which remained impaired in all domains.

The term “functional remission” is a psychiatric concept that is deﬁned as an “association of clinical remission and a recovery of social, professional, and personal levels of functioning.” In this observational study, investigators sought to determine the speciﬁc weight of psychological (anxiety and mood, coping, self-esteem) determinants of quality of life in patients with Cushing syndrome who were considered to be in clinical remission.

The cohort included 63 patients with hypercortisolism currently in remission who completed self-administered questionnaires that included quality of life (WHOQoL-BREF and Cushing QoL), depression, anxiety, self-esteem, body image, and coping scales. At a median of 3 years since remission, participants had a signiﬁcantly lower quality of life and body satisfaction score compared with the general population and patients with chronic diseases. Of the cohort, 39 patients (61.9%) reported having low or very low self-esteem, while 16 (25.4%) had high or very high self-esteem. Depression and anxiety were seen in nearly half of the patients and they were more depressed than the general population. In addition, 42.9% of patients still needed working arrangements, while 19% had a disability or cessation of work.

Investigators wrote, “This impaired quality of life is strongly correlated to neurocognitive damage, and especially depression, a condition that is frequently confounded with the poor general condition owing to the decreased levels of cortisol. A psychiatric consultation should thus be systematically advised, and [selective serotonin reuptake inhibitor] therapy should be discussed.”

Abstract

Objective Cushing’s disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD.

Design Studies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment.

Methods A two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles.

Results At the time of diagnosis, 58–85% of patients have hypertension, 32–41% are obese, 20–47% have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65–90%), but the potential for relapse remains (rates of 5–36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission.

Conclusions These findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy.

Although there have been several consensus statements published recently on the definition of remission, diagnosis, and the management of CD, the severity and diversity of the clinical scenario and associated morbidities continue to present a management challenge (1, 22, 23). Additionally, there is recent evidence of persistent deleterious effects after remission, most notably persistent elevated cardiovascular risk (3, 22). The main objective of the current literature review is to describe the current burden of the disease and to summarize data on specific aspects of this burden, which underscores the need for improved diagnostic and therapeutic approaches.

Materials and methods

Available literature were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, mortality, prevalence of comorbidities at diagnosis, reversibility of comorbidities after treatment (in particular, after disease remission), outcomes and complications of current treatment options, and HRQoL associated with CD and interventions.

The literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD. It was conducted in two stages: i) articles published between 2000 and 2012 were identified through a PubMed search using the following keywords: CD, incidence, prevalence, mortality, treatment, remission, cure, excess cortisol, outcomes, cost, QoL, morbidities, transsphenoidal surgery (TSS), adrenalectomy, radiotherapy, steroidogenesis inhibitors, ketoconazole, mitotane, aminoglutethimide, etomidate, metyrapone, pasireotide, and cortisol receptor antagonists; and ii) an additional hand search was conducted on the basis of the bibliographies of identified articles. All studies that provided data (regardless of publication year) related to these research questions were retained.

Definitions

Different criteria for defining the remission of hypercortisolism have been proposed, ranging from the occurrence of definitive or transient postoperative hypocortisolemia to the adequate suppression of cortisol after dexamethasone administration. According to a recent consensus statement (23), persistent postoperative morning serum cortisol levels of <2 μg/dl (∼50 nmol/l) are associated with remission and a low recurrence rate of ∼10% at 10 years. Persistent serum cortisol levels above 5 μg/dl (∼140 nmol/l) for up to 6 weeks following surgery require further evaluation. When serum cortisol levels are between 2 and 5 μg/dl, the patient can be considered in remission and can be observed without additional treatment for CD. A subset of patients can even develop complete adrenal insufficiency (serum cortisol levels below 2 μg/dl (∼50 nmol/l)) up to 12 weeks postsurgery (24, 25). Therefore, repeated evaluation in the early postoperative period is recommended. However, long-term follow-up is necessary for all patients because no single cortisol cutoff value excludes those who later experience disease recurrence, and up to 25% of patients develop a recurrent adenoma within 10 years after surgery (26, 27, 28).

Results

Incidence and prevalence of CD

Although epidemiologic data on CD are limited, several population-based studies indicate an incidence of 1.2–2.4 per million (14, 19) and the prevalence of diagnosed cases to be ∼39 per million population (14). Lindholm et al. (19) used the case definition as either the presence of a corticotroph adenoma or remission after neurosurgery, which yielded an estimated incidence rate of 1.2–1.7 per million per year. Etxabe & Vazquez (14) reported an incidence of 2.4 per million in Vizcaya, Spain. A large-scale retrospective survey carried out in New Zealand by Bolland et al. (29) found the approximate prevalence of all forms of Cushing’s syndrome (CS) (the majority of these cases were of pituitary origin) to be 79 per million and the incidence to be 1.8 per million per year. Differences in epidemiologic estimates may be attributable to varying case definitions (for instance, the study by Lindholm excluded cases in which the adenoma could not be localized or those that could not achieve remission from surgery), geographical differences, and temporal effects. The prevalence of CD may be underestimated due to unrecognized patients with mild symptoms and patients with a cyclic form of CD (30).

Time to diagnosis

Data on the time from onset of symptoms to diagnosis are also limited. In a prospective study by Flitsch et al. (31) of 48 patients with pituitary adenomas, including 19 who had ACTH-secreting adenomas causing CD, the reported time from onset of symptoms to diagnosis was 4.3 years. A study by Martinez Ruiz et al. (32), which was based on only four pediatric CD patients, reported the time between onset of symptoms and diagnosis as ranging from 2.5 to 5 years. Etxabe & Vazquez (14) estimated that the average time from onset of clinical symptoms to diagnosis in 49 CD patients was 45.8±2.7 months (6–144 months), thus 3.8 years. This is corroborated by the findings from a Belgian cross-sectional study on pituitary adenomas including CD, which estimated that patients experienced symptoms for an average of 45 months before diagnosis (33). However, the reliability and generalizability of these data are limited by small sample sizes and the retrospective nature of the studies. Indeed, the New Zealand data from Bolland et al. (29) report that on presentation, patients experienced symptoms for a median of 2.0 years (but ranging up to 20 years) before diagnosis. On the basis of data from the prospective European Registry on Cushing’s syndrome (ERCUSYN) (total number of patients=481, of whom 66% of patients had CD), median delay in diagnosis was 2 years (34).

Mortality in patients with CD

Mortality in patients with CD has been analyzed in several small studies, with overall rates reported as standardized mortality ratio (SMR) ranging from 1.7 to 4.8 (Table 1) (14, 15, 17, 19). In studies in which mortality was assessed among those in remission and those with persistent disease separately, patients with persistent hypercortisolemia consistently had the highest mortality risk (15, 19, 35, 36). In addition, TSS as a first-line treatment has been an important advance as high remission rates after initial surgery have been accompanied by mortality rates that mirror those observed in the general population (17, 35, 37). In a case series from the UK, it was found that the majority of deaths occurred before 1985, which was before TSS was employed as the routine first-line treatment at the center (36). In a recent retrospective study, 80 patients undergoing TSS for CD between 1988 and 2009 were evaluated, and long-term cure (defined as ongoing absence of hypercortisolism at last follow-up) was reported in 72% of patients. However, overall elevated mortality persisted in patients (SMR 3.17 (95% CI: 1.70–5.43)), including those who achieved ‘cure’ (SMR 2.47 (95% CI: 0.80–5.77)), although even higher mortality was seen in those with postoperative recurrence/persistent disease (SMR 4.12 (95% CI: 1.12–10.54) (38). Additionally, a nationwide, retrospective study in New Zealand reported significant persistently increased mortality both in macro- and microadenomas (SMR 3.5 (1.3–7.8) and 3.2 (2.0–4.8) respectively), despite long-term biochemical remission rates of 93 and 91% of patients, respectively (29).

Patients with hypothalamic-pituitary-adrenal axis dysregulations report health-related quality of life that is far lower than that of the general population, according to findings of a prospective study.

“In most centers, both patients with adrenal deficiency and patients with Cushing’s syndrome are managed by the same team,” Charlotte DeBucy, of the Center for Rare Adrenal Diseases at Cochin Hospital in Paris, and colleagues wrote. “Despite the usual perception that both types of diseases alter quality of life, few studies have similarly investigated the impact of cortisol dysregulations on [health-related quality of life]. Such studies are important, however, to identify meaningful differences that would be important to consider to improve management and outcome.”

De Bucy and colleagues analyzed data from 343 patients with Addison’s disease or Cushing’s syndrome followed in routine practice at a single center in France between September 2007 and April 2014 (78% women; mean age, 48 years; mean length of time since diagnosis, 7.8 years; 61% married). All participants completed the short-form health survey (SF-36), a survey of health-related quality-of-life measures and the 12-item general health questionnaire (GHQ-12), a measure of psychological well-being or distress. Questionnaires were completed at baseline and at 6, 12, 24 and 36 months. Patients with Cushing’s syndrome were also assessed for cortisol status at baseline and at follow-up evaluations.

Within the cohort, 206 had Cushing’s syndrome of pituitary origin, 91 had Cushing’s syndrome of adrenal origin and 46 patients had Addison’s disease; 16% were included in the study before any treatment was initiated.

Researchers found that mean standard deviation scores for psychological and physical dimensions of the SF-36 were “well below” those of the general population, but diagnosis, cortisol status and time since treatment initiation all influenced individual scores. Cushing’s syndrome of pituitary origin was associated with worse health-related quality of life, especially for physical functioning, social functioning and mental health. In Cushing’s syndrome, health-related quality of life was generally worse during periods of hypercortisolism, but scores for these patients were lower than those of patients with Addison’s disease even during periods of hypocortisolism or eucortisolism, according to the researchers.

“The differences were particularly large for physical functioning and role-physical subscales,” the researchers wrote.

They also found that mental health scores for patients with Cushing’s syndrome decreased during periods of hypocortisolism, whereas other adrenal conditions were associated with higher mental health scores.

More than half of patients, regardless of diagnosis and cortisol status, had psychological distress requiring attention, according to the GHQ-12 survey.

“Our findings are important for clinical practice,” the researchers wrote. “The consequences of cortisol dysregulation on [health-related quality of life] should be considered in the management of adrenal insufficiency and even more (in) Cushing’s syndrome patients, and these consequences can be long term, affecting apparently cured patients. Early information on these consequences might be helpful for patients who often perceive a poor quality of life as the result of inadequate disease control or treatment. Even if this possibility exists, knowing that adrenal diseases have long-lasting effects on [health-related quality of life] may be helpful for patients to cope with them.” – by Regina Schaffer

In a cross-sectional study, Eline S. van der Valk, MD, of Amphia Hospital in Breda, the Netherlands, and colleagues also found that patients with Addison’s disease reported physical activity levels that were significantly lower than those reported by other Dutch chronically ill patients.

“The clinical relevance of the impaired [quality of life] and increased fatigue found in our study is supported by the size of the differences in scores and the restriction in physical activity in patients with [Addison’s disease], an important activity in daily life,” the researchers wrote. “Physical inactivity could be very detrimental in [Addison’s disease] because the prevalence of other cardiovascular risk factors is already increased, and it has been demonstrated that patients with [Addison’s disease] have an up to twofold increased mortality rate from [CVDs].”

Researchers analyzed survey data from 328 Dutch adults with Addison’s disease on stable glucocorticoid replacement therapy with hydrocortisone or cortisone acetate (mean age, 53 years; 223 women; mean duration of disease after diagnosis, 15.6 years). Participants attended outpatient clinics at University Medical Center Utrecht and Radboud University Nijmegen Medical Centre, or were members of the Dutch Association of Addison and Cushing Patients. They completed general and health-related quality of life (Short Form 36; Checklist Individual Strength) and physical activity questionnaires. Scores were compared with a random sample of 1,718 adults who completed a Dutch National Health Survey (controls).

Within the cohort, 53% of participants had isolated Addison’s disease; 74.1% received hydrocortisone therapy; 25.9% received cortisone acetate therapy; 87.2% received fludrocortisone therapy; and 23.2% received dehydroepiandrosterone replacement therapy.

In both men and women with Addison’s disease, researchers found that quality of life scores in all component summaries were significantly decreased compared with controls, particularly in participants aged 65 years and younger. – by Regina Schaffer